In a recent study published within the Molecular Therapy journal, researchers assessed the efficacy of the scFv76 antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lung damage.

Study: Spike mutation resilient scFv76 antibody counteracts SARS-CoV-2 lung damage upon aerosol delivery. Image Credit: Thichaa/Shutterstock

For the reason that progression of coronavirus disease 2019 (COVID-19) is unpredictable, the reoccurrence of severe pulmonary disorders and the emergence of latest variants can’t be ruled out. That is primarily as a result of the uneven vaccination coverage worldwide and the waning efficacy of COVID-19 vaccines. Moreover, the commentary of diverse dangerous post-acute sequelae of SARS-CoV-2 infection, particularly those affecting the nervous and cardiovascular systems, requires the urgent development of therapeutic measures which can be easy to implement and able to controlling the infection in its early stages.

Concerning the study

In the current study, researchers assessed the efficacy of nebulized scFv76 in treating COVID-19.

The potential to compete for the binding of the SARS-CoV-2 Omicron BA.1 and BA.2 spike proteins to human angiotensin-converting enzyme-2 (hACE-2) was examined by enzyme-linked immunosorbent assay (ELISA) to evaluate its reactivity to the Omicron variants. Subsequently, using surface plasmon resonance (SPR), the binding affinity of scFv76 towards the Delta and Omicron spike proteins was evaluated. Authentic SARS-CoV-2 Delta and Omicron BA.1 viruses were used to further investigate the neutralization of infectivity using a microneutralization assay of the cytopathic effect (CPE) observed in Vero E6 cells.

scFv76 was assessed in vitro to find out its capability to inhibit SARS-CoV-2 Omicron BA.1 or BA.2 spike-induced fusion of pulmonary cells. Moreover, scFv76 ‘s antiviral neutralization potency of scFv76 was evaluated in vitro in Delta-infected lung Calu-3 cells using RT-qPCR in contrast to the non-neutralizing control antibody scFv5. By administering 1×105 TCID50 SARS-CoV-2 Delta variant by intranasal challenge, pneumonia infection in transgenic hACE2 mice was induced to research the pharmaceutical effects of the nebulized antibody.

Results

The study results demonstrated that scFv76 had the identical potency against SARS-CoV-2 Delta and might inhibit Omicron BA.1 and BA.2 spike binding to ACE2 at IC50 concentrations lower than 2.5 nM. Furthermore, Delta has a KD of 0.6 nM, while BA.1 and BA.2 have KD of 6.3 and 14.5 nM, respectively. scFv76, but not scFv5, exhibited a neutralizing effect against the SARS-CoV-2 Omicron BA.1 and BA.2 pseudotyped viruses, with IC50 values of two.84 and a couple of.47 nM, respectively. Against the Delta and Omicron BA.1 variants on this assay, scFv76 showed IC50 values of 1.99 and 6.38 nM, respectively, while the non-neutralizing antibody scFv5 had no antiviral motion.

When incubated with nanomolar quantities of the scFv76 antibody, the team noted a remarkable inhibition of the fusion between Omicron BA.1 and BA.2 spike-expressing HEL293T cells and hACE2 receptor-expressing A549 cells. With an IC50 of 13.5 nM, scFv76 was shown to suppress infection, while the control antibody showed no effect at concentrations over 200 nM.

The group of mice treated with scFv76 showed a substantial body weight recovery 4 days after infection, in contrast to the infected mice treated with vehicle. This final result was related to a roughly 100-fold decrease within the lung viral ribonucleic acid (RNA) copy number as determined by reverse transcription-quantitative polymerase chain response (RT-qPCR) and a decrease in infectious viral particles as determined by TCID50. Notably, the nebulized scFv76 significantly decreased viral RNA within the nasal turbinates and decreased the infectious virus titer within the lungs to undetectable levels in three of 5 animals.

Histopathological examination of lung sections consistently revealed a substantial decrease in lung interstitial edema, hematological endoalveolar extravasation, cellular inflammatory infiltrates within the alveolar/interstitial region, and thickening of the alveolar septum. Overall, the Delta virus-induced lung inflammation and damage may very well be greatly reduced by administering nebulized scFv76, but not phosphate-buffered saline (PBS).

Data showed that essential pro-inflammatory cytokines reminiscent of interleukin-6 (IL-6), IL-1, IL-21, IL-10, IL-4, tumor necrosis factor-alpha (TNF-α), and chemokines reminiscent of C-C motif ligand 2 (CCL2), CCL20, C-X-C motif ligand 1 (CXCL1), and CXCL-10 were significantly reduced after being exposed to scFv76 aerosol. Within the lungs of mice given scFv76 treatment, all these interferon (IFN) genes led to a marked reduction. The medication also inhibited the overexpression of molecules that cause infection-related tissue damage, including adhesion molecules, angiopoietin 2, and inflammasome effectors like nod-like receptor protein 3 (NLRP3).

The contact region of the scFv76 fragment overlapped with the ACE2 binding interface, thus matching the locations of 13 out of the 17 ACE2-binding residues on the SARS-CoV-2 receptor-binding domain (RBD). This is important because the angle of approach of scFv76 to the RBD mirrors that of ACE2. On this regard, the structural basis for the powerful scFv76 neutralizing activity was provided by the near structural similarity of the scFv76 and ACE2 binding modes to the RBD and the resulting competition for binding.

The study findings showed that scFv76 aerosol therapy could effectively reduce viral proliferation, greatly lowering lung inflammation and damage. The researchers consider that COVID-19 will be treated with scFv76 antibody aerosol therapy whatever the variant causing the infection.

Journal reference:

• Milazzo FM, Chaves-Sanjuan A, Minenkova O, Santapaola D, Anastasi AM, Battistuzzi G, Chiapparino C, Rosi A, Pich EM, Albertoni C, Marra E, Luberto L, Viollet C, Spagnoli LG, Riccio A, Rossi A, Santoro MG, Ballabio F, Paissoni C, Camilloni C, Bolognesi M, De Santis R. (2022). Spike mutation resilient scFv76 antibody counteracts SARS-CoV-2 lung damage upon aerosol delivery. Molecular Therapy. doi: https://doi.org/10.1016/j.ymthe.2022.09.010